Dear Editor,We have read with interest the recent study by van Rongen et al. comparing midazolam clearance in obese adolescents with morbidly obese adults [1]. The authors attributed a higher midazolam clearance in the obese adolescents group to higher cytochrome P450 3A enzyme activity when compared to the morbidly obese adults group. However, the surgery type in the obese adults appears to have been exclusively laparoscopic procedures, whereas the surgery in the obese adolescents appears to have been predominantly orthopaedic and otolaryngeal procedures [2,3]. Laparoscopy, with the associated pneumoperitoneum, has been shown to decrease portal venous blood flow by approximately half, with a paradoxical increase in hepatic artery blood flow by approximately 20%, and apparent effects on drug clearance [4]. This effect could also account for the apparent differences in clearance between obese adolescents and morbidly obese adults in the van Rongen et al. study. Depending on the relative timing of the dosing and the onset of the pneumoperitoneum, the effect could also mimic structural pharmacokinetic model elements, such as an extra compartment, as described in Brill et al. [3]. Have the authors considered these effects in the development of the structural model and also the covariate modelling? Some patients in the obese adolescents group underwent bariatric surgery. If these procedures were laparoscopic, then it would be interesting to explore the influence of surgery type on drug clearance. It would also be interesting to model intraperitoneal pressure during laparoscopy, if these data are available, as a covariate effect.Funding No funding was received for the preparation of this letter. Compliance with Ethical Standards Conflict of interest

Many drug-drug interactions (DDIs) in the pediatric population are managed based on data generated in adults. However, due to developmental changes in elimination pathways from birth to adolesence, and variable weight-adjusted dose of interacting drugs, the assumption of DDIs being similar in adults and pediatrics might not be correct. This study compares the magnitude of reported DDIs in pediatric and adult populations. A systematic literature review was undertaken to identify reports of DDIs in pediatric subjects. A total of 145 reports of DDIs were identified over the age range of birth to 20 years. The magnitude of DDIs for 24 drug pairs from 31 different pediatric studies could be assessed and compared with those in adults where corresponding data existed. The magnitude of the DDI, as measured by a relevant parameter (e.g., AUC, CL) in the presence and absence of inhibitor, were higher (>1.25-fold), similar (0.8-to 1.25-fold) or lower (<0.8-fold) than the corresponding ratio in adults in 10, 15, and 8 cases respectively. An age-related trend in the magnitude of DDIs could not be established. However, the study highlighted the clear paucity of the data in children younger than 2 years. Care should be exercised when applying the knowledge of DDIs from adults to children younger than 2 years of age.

The magnitude of any metabolic drug-drug interactions (DDIs) depends on fractional importance of inhibited pathway which may not necessarily be the same in young children when compared to adults. The ontogeny pattern of cytochrome P450 (CYP) enzymes (CYPs 1A2, 2B6, 2C8, 2C9, 2C18/19, 2D6, 2E1, 3A4) and renal function were analyzed systematically. Bootstrap methodology was used to account for variability, and to define the age range over which statistical differences existed between each pair of specific pathways. A number of DDIs were simulated (Simcyp Pediatric v12) for virtual compounds to highlight effects of age on fractional elimination and consequent magnitude of DDI. For a theoretical drug metabolized 50% by each of CYP2D6 and CYP3A4 pathways at birth, co-administration of ketoconazole (3 mg/kg) resulted in a 1.65-fold difference between inhibited versus uninhibited AUC compared to 2.4-fold in 1 year olds and 3.2-fold in adults. Conversely, neonates could be more sensitive to DDI than adults in certain scenarios. Thus, extrapolation from adult data may not be applicable across all pediatric age groups. The use of pediatric physiologically based pharmacokinetic (p-PBPK) models may offer an interim solution to uncovering potential periods of vulnerability to DDI where there are no existing clinical data derived from children.

The hepatic extraction ratio (E H ) is commonly considered an "inherent attribute" of drug. It determines the main physiological and biological elements of the system (patient attributes) that are most significant in interindividual variability of clearance. The E H